Multiple myeloma (MM) represents the continued proliferation of a terminal differentiated B cell. MM cells share the properties of normal plasma cells such as high protein production and hardiness but differ in that MM cells continue to proliferate and express c-Myc despite their terminal differentiated state. The proliferative program of MM is coordinated by transcription factors and chromatin-associated factors. Transcription factors such as MYC, NFGB, MAF and XBP1 are linked to disease pathogenesis, tissue specificity, and drug resistance. Several of these factors are overexpressed in MM through aberrant linkage of the immunoglobulin promoter to the TF gene. Furthermore, sequence analysis of the MM genome revealed that amongst the genes mutated or deleted in MM, there is over-representation of chromatin regulatory factors. The centrality of histone methylation in MM was firmly established by the discovery that a lysine methyltransferase (MMSET) is rearranged and activated in poor prognosis t(4;14)-associated MM. Additional research from our group and others found that MM proliferation is dependent on the bromodomain and extra-terminal (BET) domain family of proteins (BRD2, BRD3 and BRD4) and their ability to support the transcriptional program of c-MYC. Together these findings create our central hypothesis that aberrant gene regulation underlies the biology of MM, and that these anomalies can be therapeutically targeted. Building on our mutual interest in chromatin biology, we have undertaken a collaborative program to study and target BRD4 and MMSET in MM. Hypotheses: Aberrant overexpression of Myc in a differentiated plasma cell remains a central paradox of and driver of MM. Transcriptional signaling, which underlies the pathogenesis of MM, requires the co-activator function of BET bromodomains. Direct inhibition of BET bromodomains alone and in combination comprises a powerful therapeutic strategy in MM. The MMSET lysine methyltransferase, which is found in complex with BRD4, stimulates myeloma pathogenesis through global changes in histone modification and gene expression. The oncogenic activity of MMSET is closely linked to its histone methylation activity and MMSET and BRD4 represent compelling molecular targets for development of new MM therapies. We will pursue following Specific Aims: Aim 1. To characterize the role of BET bromodomains in epigenetic bookmarking of the Myc and E2F transcriptional programs.Aim 2. To study domains of MMSET amenable for therapeutic targeting, guided by crystallographic structures, and develop MMSET inhibitors as chemical probes and lead therapeutics. Aim 3. To translate BET and MMSET inhibitors to therapeutic use in patients with MM.